P18 SKIN EXPRESSION OF P16INK4A, A BIOMARKER FOR CELLULAR SENESCENCE, DOES NOT PREDICT FRAILTY OR TREATMENT OUTCOME IN NEWLY DIAGNOSED MULTIPLE MYELOMA
Authors: F. Smits, K. Groen, C. Stege, M. Seefat, I. Nijhof, N. van de Donk, P. Ypma, S. Zweegman
Journal: HemaSphere (2023)

Introduction: The clinical outcome of older patients with multiple myeloma (MM) is heterogeneous, largely depending on frailty level. To assess frailty, clinical scores such as the International Myeloma Working Group frailty index (IMWG-FI) are used to distinguish between ‘fit’, ‘intermediate-fit’ and ‘frail’ patients. However, as the discriminative power of these scores is still insufficient to guide treatment choices, there is an unmet need for novel biomarkers that reflect biological age (‘frailty’) – rather than chronological age. The cell cycle regulator and tumor suppressor p16INK4a has been found to be a robust biomarker of cellular senescence and aging. Previous studies showed that p16INK4a markedly increases with age and p16INK4a inactivation partially reverses age-related phenotypes. p16INK4a positive cells in skin biopsies have also been found to be reflective of a person’s biological age. We therefore investigated whether p16INK4a expression in the skin is associated with frailty and could predict treatment outcomes in older patients with Newly Diagnosed Multiple Myeloma (NDMM). Methods: We evaluated p16INK4a expression in skin biopsies taken at baseline from newly diagnosed MM patients who were included in two prospective trials: the HOVON 123 and HOVON 143 study, including intermediate-fit and frail patients based on the IMWG-FI. Before start of treatment, biopsies were obtained from non-sun exposed skin (area above the bone marrow aspirate site at the posterior iliac crest). p16INK4a expression was defined as two variables: the number of p16INK4a positive cells 1) in the basal membrane, normalized to length of the basal membrane (mm) and 2) in the entire epidermis, normalized to the surface of the epidermis (mm2). Because p16INK4a positivity was not normally distributed, p16INK4a positivity was classified in tertiles (low < 0.93/mm, intermediate 0.93 – 3.03/mm, high > 3.03/mm). Statistical analysis was performed using the Wilcoxon signed-rank test and univariate Cox regression. Results: Prior to treatment initiation skin biopsies were obtained from 305 NDMM patients with a median age of 78 years (range 65 – 92). Median number of p16INK4a positive cells in the basal membrane was 1.75 per mm (range 0 – 30.8/mm) and 41.5/mm2 (range 0 – 850.5/mm2) in the epidermis. We found no significant difference in p16INK4a positivity in the basal membrane (1.55/mm vs 1.96/mm; p=0.26) or in the epidermis (38.0/mm2 vs 48.5/mm2; p=0.20) between the intermediate-fit and frail patients. Moreover, p16INK4a expression was not associated with progression free survival or overall survival (Figure 1). Conclusion: p16INK4a expression in the skin is not associated with frailty level or treatment outcome in intermediate fit and frail NDMM patients. Recent literature suggests that p16INK4a mRNA expression in peripheral T cells could be a more accurate marker for cellular senescence. Based on our results, we discourage the evaluation of p16INK4a protein levels in skin biopsies to improve frailty assessment in older patients with newly diagnosed MM.